CDU Contributing Editor

SAN DIEGO, California Compared to the sunny weather outside, attendees at the 29th annual International Stroke Conference inside the beautiful San Diego Convention Center in early February were confronted with the ongoing frustrations of limited therapeutic options for the 750,000 often-devastating strokes that occur annually in the U.S.

Although this meeting, sponsored by the American Stroke Association (Dallas, Texas), is heavily sponsored by the pharmaceutical industry, which markets post-ischemic stroke thrombolytics (tPA) and stroke prevention medications (Plavix and others), there continues to be tremendous interest in device-based solutions as well. For example, it is well known that a significant percentage of ischemic stroke, which accounts for 80% to 85% of all strokes, is caused by the migration of embolic material from the carotid arteries into the vasculature of the brain.

For the past 50 years, the treatment of carotid artery disease has been dominated by carotid endarterectomy (CEA), which is the most commonly performed major vascular surgery procedure in the U.S. today. An estimated 175,000 carotid endarterectomies were performed in the U.S. in 2003, with another 100,000 procedures done in other countries.

The number of CEAs has doubled in the past 10 years, sparked by several major clinical trials in the 1990s that definitively demonstrated that CEA provides significantly better protection against embolic stroke than does medical management for both symptomatic and asymptomatic patients.

However, as has been seen in several other areas of surgery, less-invasive techniques and devices have begun to encroach on the "gold standard" surgical protocol. In the case of carotid artery disease, the advent of carotid artery stents and the subsequent availability of embolic distal protection devices that capture micro-embolic material that can become dislodged during the procedure, has enabled carotid artery stenting (CAS) to challenge carotid endarterectomies.

In the past several years, somewhere between 15 and 20 trials worldwide have been initiated to compare CEA to CAS, as the upstart and aggressive interventional community, mainly cardiologists, try to show that CAS is superior. Thus far, the results reported for major CAS trials, such as Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) and AccuLink for Revascularization of Carotids in High-Risk Patients (ARCHeR), have been for the high-risk, symptomatic patient cohort who generally are not ideal CEA candidates.

One-year results for SAPPHIRE, the first multi-center, randomized study comparing CEA to CAS in high-risk patients, were presented last September at the Transcatheter Cardiovascular Therapeutics conference. The study employed the Precise nitinol self-expanding stent from the Cordis Endovascular (Warren, New Jersey) division of Cordis (Miami Lakes, Florida), a unit of Johnson & Johnson (New Brunswick, New Jersey), in combination with the Angioguard embolic protection system. Based upon numerous endpoints, CAS demonstrated excellent safety and efficacy, with the 30-day major adverse event rate for CAS at 5.8% compared to 12.6% for endarterectomy.

The multi-center ARCHeR trial, sponsored by Guidant (Indianapolis, Indiana), has demonstrated excellent safety and efficacy, although the trial was not randomized. Its impressive preliminary 30-day results were presented last spring at the annual meetings of both the American College of Cardiology (ACC; Bethesda, Maryland) and the Society of Interventional Radiology (Fairfax, Virginia). One year follow-up data, which industry sources expected to be robust, were to be presented in early March at the ACC's annual scientific sessions in New Orleans, Louisiana.

Given the red-hot controversy that is brewing in the treatment of carotid artery disease, it was not surprising that a conference session titled "Update on Carotid Stents and Trials" was one of the best-attended of the meeting. The session was moderated by Robert Hobson, MD, a vascular surgeon from the University of Medicine and Dentistry School of New Jersey (Newark, New Jersey) and the principal investigator for the National Institute of Neurological Disorders and Stroke (NINDS; Bethesda, Maryland)-sponsored trial known as the Carotid Revascularization Endarterectomy Stenting Trial (CREST). This beleaguered study, which was originally intended to commence in 1999 but has suffered interminable delays, was designed to address moderate-risk, symptomatic patients. After a very slow start, the trial has recently developed some momentum and of this writing has randomized 152 to either a CEA or CAS. Patients in the latter arm are receiving the Acculink stent and the Accunet embolic protection device, both manufactured by Guidant.

A total of 2,500 patients from 60 North American centers will ultimately be enrolled in CREST over the next two to three years. Thus, final results are not expected for several years, which means that the resolution of the controversy of CEA vs. CAS in moderate-risk, symptomatic patients will be delayed.

Nick Hopkins, MD, a noted vascular surgeon and interventional neuroradiologist from the State University of New York (Buffalo, New York), discussed the results of the Carotid Revascularization Endarterectomy or Stenting Systems (CARESS) trial, which he said was treating a "real-world population" of both high- and low-risk patients. This non-randomized but prospective trial has completed the Phase II portion, with 450 patients randomized to CEA vs. CAS on a 2:1 basis. Both arms have demonstrated an approximate 2% rate of 30-day major adverse events.

Hopkins noted that the FDA has given the CARESS trial investigators the go-ahead for a full-blown study of 3,000 patients, but that funding from industry is lacking thus far. If CARESS did get funded and completed, it would be a "path to the real-world treatment of CEA and CAS," he said. Further, Hopkins indicated that CAS appears to be as durable as CEA and that the procedure's excellent results are due to the "incredible technology brought to the medical community by industry."

Stephen Ramee, MD, an interventional cardiologist from the Ochsner Clinic (New Orleans, Louisiana), took a decidedly aggressive approach in his talk. He said he had "no doubt" that CAS will ultimately become the standard of care for carotid artery occlusions and will replace CEA. He reviewed numerous clinic trials from around the world, saying that a meta-analysis of 3,500 high-risk, symptomatic patients showed a stroke rate of 2.0% and a combined stroke/death rate of 6.6%, which he said were "well within" the American Heart Association's (Dallas, Texas) guidelines for carotid endarterectomy, which were issued in 1998.

Ramee lashed out at both the FDA and the Centers for Medicare & Medicaid Services (CMS; Baltimore, Maryland), saying that based on the data from around the world, it was "unconscionable" that carotid artery stenting had not received FDA approval and that reimbursement was lacking.

Industry experts believe that Cordis Endovascular will attain the first CAS approval from the FDA sometime this year. However, the timing of a reversal of the CMS non-coverage reimbursement decision on CAS remains less clear.

Narrow 'window' frustrates medical community

Ischemic stroke accounts for an estimated 80% to 85% of the 750,000 strokes that occur annually in the U.S. Thus it was not surprising that researchers and attendees at the conference focused considerable attention on technologies to expand treatment options for ischemic stroke.

The FDA approval in 1996 of the powerful clot-busting drug tissue plasminogen activator (tPA) developed by Genentech (South San Francisco, California) was hailed as a major breakthrough in the fight against acute ischemic stroke. There is no doubt that tPA is efficacious, as the original National Institute of Neurological Disorders and Stroke trial demonstrated an impressive 30% reduction in severe disability in ischemic stroke patients who received tPA.

However, tPA must be administered systemically within three hours of stroke symptom onset in order to achieve its maximum therapeutic effect and minimize the risk of intracerebral hemorrhage (ICH), which occurs in about 6% to 7% of patients treated. ICH can occasionally be fatal.

While appreciating the vastly improved performance of tPA relative to other alternatives that were used before tPA's approval, the stroke community remains very frustrated, as the impact on actual patient therapy has been minimal. Various studies have shown that only about 2% to 4% of patients suffering from acute ischemic stroke are currently treated with tPA thrombolytic therapy. In fact, a presentation by Vanja Douglas of the University of California San Francisco Medical Center (San Francisco, California) noted that at primary stroke centers established by the Brain Attack Coalition only 2.4% of all patients arriving at a hospital emergency room (ER) with an acute ischemic stroke received tPA.

There are numerous explanations for this bleak enrollment rate, including the oft-subtle symptoms of ischemic stroke (especially compared with an acute heart attack) that cause patients to delay their departure to the hospital, the limitations of current diagnostic technologies, inadequate physician reimbursement and the lack of a written protocol and trained staff at ERs.

These factors have significantly hampered the rate of acute ischemic stroke treatment and do not overcome the intense educational efforts that have been made by organizations such as the American Stroke Association and the National Stroke Organization (Englewood, Colorado) to educate the public. For example, the slogan "time is brain" has been a major theme to inform the public that rapid treatment is critical to mitigating the potentially devastating impact of an ischemic stroke.

The stroke community has set an ambitious goal to deliver thrombolytic therapy to 20% to 25% of ischemic stroke patients. Achievement of this goal will require a Herculean effort to improve technology, delivery systems and public education, but perhaps more importantly, develop new thrombolytic agents and other modalities that lengthen the "therapeutic window" of opportunity.

At past stroke conferences, hope has arisen that a new pharmaceutical compound with a longer time window could boost the treatment rate for ischemic stroke victims. These hopes have been consistently dashed as either the feasibility or pivotal clinical trial has demonstrated unacceptable toxicity or lack of efficacy.

A new compound, which is so promising that it was recently selected as one of the American Heart Association's "Top 10 advances for 2003," was one of the highlights of this year's meeting.

This new clot-busting substance, a genetically engineered thrombolytic enzyme, was originally found in the saliva of vampire bats, where its role is to support the feeding activity of the bat. Generically called Desmodus rotundus salivary plasminogen activator, or desmoteplase, it acts in a similar way to tPA but works almost exclusively by targeting and destroying fibrin, the structural scaffold of blood clots. It is able to dissolve the blood clot with less risk of ICH than tPA and may even have neuroprotective properties.

Human clinical trials have been under way for more than two years and are very promising. At this year's meeting, the developer, PAION GmbH (Aachen, Germany), released the results of the second phase of the Desmoteplase in Acute Ischemic Stroke (DIAS) trial. This multi-center, placebo-controlled, randomized dose-finding European, Australian and Asian study recruited a total of 102 patients, who were treated in a three- to nine-hour time window. Their neurological scores were measured between days four and 20 and then were followed for 90 days.

The trial showed that the drug improved reperfusion and resulted in a much better clinical outcome as measured by several widely accepted neurological measures. Some 60% of patients achieved the pre-defined clinical endpoint with an excellent safety profile.

A sister study called the Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke (DEDAS) is now ongoing at 17 centers in the U.S., using the same study design. Results of DIAS and DEDAS will be pooled so that there will be more statistical significance.

Both trials are using magnetic resonance imaging (MRI) as a key inclusion criteria to identify patients who will benefit the most from this regimen. This represents an important departure from earlier clinical trials, which strictly limited thrombolytic therapy based on a rigid time window. MRI can identify and quantify the amount of tissue that is still alive due to collateral or adjacent blood flow. Patients with this penumbra, or an area of brain that can be salvaged by restored blood flow, will likely benefit from the MR imaging approach.

Anthony Furlan, MD, the principal investigator of DEDAS and medical director of the Cerebrovascular Center at The Cleveland Clinic (Cleveland, Ohio), told Cardiovascular Device Update that "this physiological approach to patient selection is an important advance in the emergent treatment of acute stroke." Going forward, patients will not only be evaluated for the time window but their physiological parameters also will be an important determinant in whether they qualify for thrombolysis. Furlan described the new agent as a "possible blockbuster that would cause a paradigm shift in ischemic stroke therapy."

Several other options are being explored to enhance acute ischemic stroke therapy. The glycoprotein IIb/IIIa inhibitor Reopro, which has been used by interventional cardiologists for years, showed promising results in the Phase IIb Abciximab in Emergent Stroke Treatment Trial (AbESTT) for up to six hours after symptom onset. These results were reported at last year's stroke meeting. A larger, 1,500-patient Phase III trial is now under way.

Hypothermia remains another area of significant potential to lengthen the therapeutic window, with several companies and institutions pursuing this avenue. According to Ludmila Belayev, MD, of the department of neurology at the University of Miami School of Medicine (Miami, Florida), "hypothermia appears to confer some neuroprotective benefits but more work needs to be done to define its exact role."

A mechanical corkscrew-like device for embolic material removal, developed by privately owned Concentric Medical (Mountain View, California), is showing promise for the swift capture and removal of ischemic clots. Favorable results of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial were reported at this meeting and a pivotal trial is ongoing.

Finally, stroke researchers continue to be intrigued by the potential for combined therapy that involves the use of both systemic intravenous and direct intra-arterial thrombolytics and by various devices that can deliver thrombolytics directly to the ischemic site.